The etiology and pathogenesis of human and animal primary hepatomas remains largely unknown. The extrahepatic administration of diethylnitrosamine to rats results in the development of a high incidence of primary liver tumors. Since the N-nitroso compounds occur commonly in nature and human contact with these agents has proven to be extremely likely, it is proposed to use this specific hepatocarcinogenic agent as a molecular model for the study of the induction and development of primary neoplasms. The major objective of this proposal will be to investigate both genetic and epigenetic alterations induced by diethylnitrosamine in the normal cellular regulatory circuits which govern selective gene expression. Several model systems will be used in the proposed research to study diethylnitrosamine induced alterations in differential gene expression. These model systems include the following: normal adult rat liver; chemically or surgically induced regenerating rat liver; rat liver undergoing chemically induced neoplastic transformation; fetal rat liver; and fully developed diethylnitrosamine induced rat hepatomas. Nucleic acid liquid hybridization techniques will be employed to quantitatively monitor general changes in the genetic expression of both repetitive and unique RNA transcripts in normal, regenerating, neonatal and chemically transformed rat liver. Nucleic acid reassociation procedures will also be used to monitor alterations in the expression of the genes which code for rat serum albumin and alpha-fetoprotein in normal, proliferating, fetal and carcinogen exposed rat liver cells. The information gained from this study will contribute to our understanding of the nature of the critical biochemical alterations induced in cells by chemical carcinogens and thus will ultimately aid in the development of rational cancer therapeutic agents.